Formation of Regioisomers

The coupling of bromo- or iodobenzene to styrene yields regioselectively a mixture of E- and Z-stilbenes 12 and 13. An electron-withdrawing substituent at the olefinic double bond often improves the regioselectivity, while an electron-donor-substituted alkene gives rise to the formation of regioisomers. 

The preparation of cyclopentadienes with up to four trimethylsilyl groups can be performed easily on a large scale starting with monomeric cyclopentadiene by repeated metalation with n-butyllithium and treating the resulting anion with chlorotrimethylsilane [84], Any complication caused by formation of regioisomers does not occur, since all trimethylsilyl-substituted cyclopentadienes are fluxional by virtue of proto- and silatropic shifts [85], Upon deprotonation with n-butyllithium the thermodynamically most favorable anion is formed selectively (Eqs. 20, 21). Thus, metalation of bis(trimethylsilyl)cyclopentadiene 74, which exists preferentially as the 5,5-isomer, selectively affords the 1,3-substituted anion 75. Similarly, tris(trimethylsilyl)cyclopentadiene 76, which is found to be mainly as the 2,5,5-isomer, affords the 1,2,4-substituted anion 77. 

Photocyclization (A = 300nm) of an imidic cysteine derivative 216 results in the formation of regioisomers 217 and 218 in an 81 19 ratio (Equation 25) <2000JOC7151>. 

Copper-catalyzed cyclopropanation of benzene and its derivatives by a diazoacetic ester yields a norcaradiene 230 which undergoes spontaneous ring opening to cyclo-heptariene 231. At the temperatures needed for successful cyclopropanation, sigma-tropic H-shifts leading to conjugated isomers of cycloheptatriene carboxylates cannot be avoided. The situation is complicated by the formation of regioisomers upon cyclopropanation of substituted benzenes, and separation of the cycloheptatriene isomers may became tedious if not impossible. 

The results describing formation of regioisomers in the case of MCR involving 3-amino-l,2,4-triazole, aldehydes, and pyruvic acid were also published [62]. The treatment was carried out in boiling DMF and a mixture of two regioisomeric compounds 30 and 49 (Scheme 22) were isolated and characterized (49 without separation). 

A further modification of the same process is shown in Equation (14). Using an iminoyl chloride, generated in situ from a nitrile, as the nucleophilic trap leads to the exclusive formation of regioisomer 37. The same regiochemistry was observed in the formation of compound 60 (Equation 15) <2002MOL756>. 

In addition to the formation of regioisomers, vinyl substitution and hydrogenation also take place in the presence of rhodium catalysts.413... 

When the size of the terminal alkyl-substituent became smaller, the formation of regioisomer was noted (Scheme 8E.18) [72]. On the other hand, the regioselectivity was increased from 2.5 1 to 5.7 1 by using a bidentate ligand, and dramatically to 10 1 by using a chiral ligand,... 

Whereas FMO theory correctly predicts the regioselectivity for cycloadditions in simple alkyl-substituted olefinic systems,51,58 extension of similar calculations for cycloadducts (7a,b-lla,b)120 predicts the formation of regioisomer a, although, except in the case of 7 and 8, the b isomer is the predominant one. The differences between prediction and experiment in stereoselectivity have been attributed primarily to double bond rehybridization arising from double bond distortion in bridgehead olefins,142 which also explains their enhanced reactivity.96,120 Also double-bond deformation that will alter the normal mixing of alkyl substituent orbitals with localized rc-bond orbitals may explain the unexpected formation of 8b.120 Attempts to explain the formation of the b isomers, based on a two-step diradical mechanism, also have failed.120... 

The formation of regioisomers is due to the presence of several sets of nonequivalent vicinal hydrogens of similar but not identical reactivity. The resulting mixture of similar products must be separated if only one of the regioisomers is desired. Since the alkene isomers are very similar in physical properties, such separations can be very difficult and certainly are not practical. 

The above problems of concomitant formation of regioisomers (as well as products resulting from disproportionation of various dihydro intermediates) have been successfully surmounted by an unequivocal synthesis of 2-amino-3-cyano-5-halomethylpyrazines (16a,b) and their corresponding 1-oxides (28a,b), which can then be utilized for the construction of isomer-free 6-substituted pteridines and pterins (Scheme 3.3a). Thus, condensation of / -chloropyruval-doxime or / -bromopyruvaldoxime, derived from diketene by chlorination or bromination, respectively, with aminomalononitrile tosylate in 2-propanol gives the 2-amino-3-cyano-5-halomethylpyrazine 1-oxides (28a) and (28b). Deoxygenation to (16a) and (16b) is readily accomplished with phosphorus trichloride [47]. 

Although polyfluoro-l,4-cyclohexadienes contain two isolated double bonds, fluorination of these compounds proceeds under milder conditions than those in fluorination of the corresponding cyclohexenes and usually leads to formation of regioisomers ... 

Addition of sulfur chlorides and sulfenyl halides to hydrocarbon olefins is a classic example of electrophilic reaction which usually proceeds under mild conditions and results in stereospecific trans-addition via intermediate formation of cyclic episulfonium cation [134]. Ring-opening reactions of episul-fonium cation with nucleophile is responsible for formation of regioisomers when nonsymmetrical olefins are used as substrates. 

Application of silanes and metalation chemistry offers an access to substituted aromatic compounds, which are difficult to prepare by classical electrophilic substitution because of harsh reaction conditions and formation of regioisomers. 

Regioselectivity in the formation of regioisomers is also observed in electrophilic aromatic substitution reactions. In the case of monosubstituted benzene derivatives, there are three possible regiosomeric products that form at different rates, based on the mechanism of the reaction (see Figure 13). see also Berzelius, Jons Jakob Chirality Dalton, John Davy, Humphry Molecular Structure Scheele, Carl Wohler, Friedrich. 

In order to probe the reactivity of the C-7 position, without the possible complication of the formation of regioisomers, 4,6-dimethoxy-2,3-diphenylindole 3a was prepared by the Bischler reaction from 3,5-di-methoxyaniline and benzoin.3 Vilsmeier formylation occurred smoothly to give the 7-carbaldehyde 4a in 82% yield. In a related manner, the other 2,3-disubstituted-4,6-dimethoxyindoles 3b-d3 were converted in yields of 62-70% to the corresponding 7-carbaldehydes 4b-d4,5 (Scheme 2). More recently, the tetrahydrocarbazole 3e6,7 was also formylated at the equivalent 8-position in 82% yield.7... 

Various functionalized alkynes can be submitted to carbocupration reactions, such as alkoxyalkynes,150 alkynyl carbamates,151 acetylenic orthoesters,152 and thioalkynes.153 The carbocupration of orthoesters, for example, 204, has been used to prepare a-substituted esters of the type 206 by acidic hydrolysis of the adduct 205 (Scheme 51).152 This allows the formation of regioisomers that are not accessible by copper-mediated addition to acetylenic esters. A stereoselective synthesis of trisubstituted alkenes has been described by Normant et al.lSd> starting from phenylthio-acetylene 207. Carbocupration with lithium di- -butylcuprate affords the intermediate 208 which, upon addition of /z-butyllithium, undergoes a 1,2-metalate rearrangement to the vinylcuprate 209. The latter can be trapped with various electrophiles, for example, ethyl propiolate, providing product 210 with complete regio- and stereocontrol. 

With conjugated or cumulated C=C bonds, one bond may respond locoselectively but with the formation of regioisomers as well (31 and 32 equation 26). Since one of the regioisomers (32) is an allylic aluminum compound, it can generate its allylic isomer (33) as well. 

To facilitate the coupling reaction of alkenylsilanes, benzenediazonium salts could be employed in place of aryl halides [4], However, the coupling reaction is sometimes accompanied by the formation of regioisomers [Eq.(4)J. This fact is ascribed to a mechanism that involves carbopalladation of an arylpalladium complex to alkenylsilanes followed by elimination of the silyl group and the palladium metal, as is the case in Heck-type reactions. 

Isotope-labeling experiments and the secondary formation of regioisomers show that the Pictet-Spengler condensation may be reversible under more vigorous conditions. ... 

In order to avoid the difficulties which could be encountered with Claisen condensations, such as formation of regioisomers, competing O-acylation, proton exchange between the enolate and the product diketone, and generally poor yields, new synthetic approaches to modified and functionalized /3-diketones in R1, R2, and/or R3 positions have been developed. 

Most of the homodimerization and -oligomerization reactions of substituted methylenecyclopropanes have been performed with nickel catalyst systems. The product composition is additionally complicated by the formation of regioisomers. With an increasing number of substituents, some general changes in the product distribution have been observed ... 

The formation of regioisomers is explained in terms of a stepwise diradical mechanism, found for [2+2]cycloadditions of C12C=CF2 (267). Because a chloro substituent stabilizes an alkyl radical more efficiently than a fluoro substituent, only two diradicals like 298 and 299 have to be considered as intermediates. The formation of regioisomeric products is taken as evidence for small energy differences between the tertiary (bridgehead) and secondary radical in the bicyclic systems studied. Although the data indicate a rate-enhancing effect in these cycloadditions, a crude evaluation of the relationship between olefinic strain of norbornene and 69 leads to the conclusion that the olefmic strain difference contributes little to the rate ratio (237). 

Two sets of conditions have been developed for electron-rich heterocycle arylation [94, 95], Most acidic heterocycles such as benzoxazole or benzothiazole may be arylated by employing fBuOLi base, aryl iodide, and DMF solvent (Scheme 23). These reactions proceed at 140 °C in minutes. For less acidic imidazole, 1,2,4-triazole, and caffeine derivatives a stronger fBuOK base is required, and the reaction proceeds by a benzyne-type mechanism. Formation of regioisomer mixtures was observed if substituted aryl halides were used in combination with fBuOK (Scheme 23). 

Figure 5.1 Formation of regioisomers in a typical Heck reaction.

Hydrocarbon and partially fluorinated olefins also undergo cycloaddition with fluorinated ketones. Thus, UV-induced addition of HFA to ethylene, vinyl fluoride, vinylidene fluoride, 1,2-difluoroethylene," trifluoroethylene, and 3,3,3-trifluor-opropylene was reported to afford corresponding oxetanes in the yield >70%. In all cases where it is possible, the formation of both regioisomers was observed. For example, irradiation of the equimolar mixture of HFA and CF2=CH2 resulted in high-yield formation of regioisomers 5 and 6 (Scheme 2.5). 

The cocycloaddition of 3-methoxybenzyne (2), though complicated by the formation of regioisomers, also proceeds with high chemoselectivity. The use of Pd(PPh3)4 as catalyst affords a mixture of phenanthrenes 107 and 108 (overall yield 84%) and small amounts of naphthalene 109 (7%), while Pd2(dba)3 promotes the formation of naphthalene 109 in 82% yield (Scheme 24) [63]. 

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